Tonotopy, the orderly representation of sound frequency is a fundamental organizing principle of the auditory system. However, the mechanisms by which precise tonotopy is established in the developing brain are poorly understood. The long term goal of this research program is to elucidate these mechanisms in the lateral superior olive, a primary sound localization nucleus in the auditory brainstem of mammals. Previous studies on the development of the two major afferent pathways to the LSO, the excitatory pathway from the cochlear nucleus (CN) and the inhibitory pathway from the medial nucleus of the trapezoid body (MNTB), indicate that tonotopic refinement of the inhibitory MNTB-LSO pathway involves three major steps - synaptic silencing, synaptic strengthening, and axonal pruning. Each of these processes occurs during a distinct developmental period which is characterized by distinct synaptic properties and activity patterns. We hypothesize that these transient properties are crucial for the implementation of specific refinement steps. We propose testing this hypothesis by delineating the role of the transition from depolarizing to hyperpolarizing responses at MNTB-LSO synapses and activity-dependent synaptic plasticity at excitatory CN-LSO synapses. To achieve these goals we will employ a combination of physiological and anatomical techniques that will be applied to brainstem slices prepared from neonatal and juvenile wild-type and genetically altered mice. Specifically, we will use whole-cell recordings to characterize the development of synaptic properties and synaptic plasticity, focal photolysis of caged glutamate to map functional connectivity between the MNTB and LSO, and reconstruction and quantitative analysis of single MNTB axon terminal fields. Results from these studies will provide important insight into the cellular and synaptic mechanisms that govern tonotopic refinement in the mammalian brain. Detailed information about these mechanisms is essential to the understanding of the biological and developmental basis of human auditory processing deficits, including deficits in speech perception or developmental dyslexia, that are associated with abnormal auditory processing on the level of the auditory brainstem. PUBLIC HEALTH RELEVANCE: This research is aimed to provide insight into the cellular mechanisms by which precise neuronal connections in the mammalian auditory system become established during development. Information about these mechanisms is important for understanding the cause of auditory processing deficits that are associated with developmental dyslexia, impairments in speech perceptions, and autism.